Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters.

Introduction: Immunocompromised patients have been shown to have an impaired immune response to COVID-19 vaccines. Methods: Here we compared the B-cell, T-cell and neutralizing antibody response to WT and Omicron BA.2 SARS-CoV-2 virus after the fourth dose of mRNA COVID-19 vaccines in patients with hematological malignancies (HM, n=71), solid tumors (ST, n=39) and immune-rheumatological (IR, n=25) diseases. The humoral and T-cell responses to SARS-CoV-2 vaccination were analyzed by quantifying the anti-RBD antibodies, their neutralization activity and the IFN-γ released after spike specific stimulation. Results: We show that the T-cell response is similarly boosted by the fourth dose across the different subgroups, while the antibody response is improved only in patients not receiving B-cell targeted therapies, independent on the pathology. However, 9% of patients with anti-RBD antibodies did not have neutralizing antibodies to either virus variants, while an additional 5.7% did not have neutralizing antibodies to Omicron BA.2, making these patients particularly vulnerable to SARS-CoV-2 infection. The increment of neutralizing antibodies was very similar towards Omicron BA.2 and WT virus after the third or fourth dose of vaccine, suggesting that there is no preferential skewing towards either virus variant with the booster dose. The only limited step is the amount of antibodies that are elicited after vaccination, thus increasing the probability of developing neutralizing antibodies to both variants of virus. Discussion: These data support the recommendation of additional booster doses in frail patients to enhance the development of a B-cell response directed against Omicron and/or to enhance the T-cell response in patients treated with anti-CD20.

Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters (preprint)

Immunocompromised patients have been shown to have an impaired immune response to COVID-19 vaccines. Here we compared the B-cell, T-cell and neutralizing antibody response to WT and Omicron BA.2 SARS-CoV-2 virus after the fourth dose of mRNA COVID-19 vaccines in patients with hematological malignancies (HM, n=71), solid tumors (ST, n=39) and immune-rheumatological (ID, n=25) diseases. We show that the T-cell response is similarly boosted by the fourth dose across the different subgroups, while the antibody response is improved only in patients not receiving B-cell targeted therapies, independent on the pathology. However, 9% of patients with anti-RBD antibodies did not have neutralizing antibodies to both virus variants, while an additional 5.7% did not have neutralizing antibodies to Omicron BA.2, making these patients particularly vulnerable to SARS-CoV-2 infection. The increment of neutralizing antibodies was very similar towards Omicron BA.2 and WT virus after the third or fourth dose of vaccine, suggesting that there is no preferential skewing towards either virus variant with the booster dose. The only limited step is the amount of antibodies that are elicited after vaccination, thus increasing the probability of developing neutralizing antibodies to both variants of virus. Hence, additional booster doses are recommended to frail patients.

Performance of prognostic scoring systems in patients with COVID-19 interstitial pneumonia in Acute Medical Unit (preprint)

Background: The early detection of COVID-19 patients with interstitial pneumonia at high risk of dismal outcome is necessary to deliver proper care and optimize management of limited resources. Objective: The aim of this study was to analyse the performance of pre-existing scores in predicting in-hospital mortality and ICU transfer at admission in an Acute Medical Unit. Methods: 106 consecutive patients with acute respiratory failure due to COVID-19 interstitial pneumoni admitted to Acute Medical Unit were enrolled. The performances of NEWS, SIRS, RAPS, REMS, qSOFA, APACHE II, CURB-65 and PSI were analysed by the Area Under the Receiver Operator Characteristic (AUROCs) and standard indices of accuracy. Results: Considering in-hospital mortality PSI and APACHE II had the higher AUROCs, 0.83 (95% CI 0.75-0.91) and 0.80 (95% CI 0.71-0.88), followed by REMS, 0.77 (95% CI 0.67-0.86), and CURB-65, 0.73 (95% CI 0.63-0.82), whereas the AUROCs of the other scores were < 0.7. PSI and APACHE II had good sensitivity (0.92 and 0.97), negative predictive value (0.96 and 0.97) and negative likelihood ratio (0.1 and 0.1), accurately identifying patients at low risk to die. However, the low specificity (0.70 and 0.47) and positive likelihood ratio (3.1 and 1.8) could limit their usefulness in predicting in-hospital mortality. Considering ICU admissions all the scores, except NEWS, SIRS and qSOFA, showed a worse performance. Conclusions: PSI and APACHE II showed good prognostic results in predicting in-hospital mortality but no pre- existing score validated for acute care settings was totally satisfactory to predict adverse outcomes in COVID-19 interstitial pneumonia after admission to Acute Medical Unit. The application setting and selected outcome criteria should always be considered to evaluate and compare scoring systems’ performance analysis.

Excellent response to high-dose intravenous immunoglobulin in anti-PF4 positive cerebral thrombosis following Ofxord-AstraZeneca AZD1222 vaccine (preprint)

One week after Oxford-AstraZeneca COVID-19 vaccine (AZD1222), a 40-year-old woman who did not report previous SARS-Cov2 infection developed headache resistant to analgesics, then nausea and vomiting. On admission, the neurological examination was negative and haematological exams showed thrombocytopenia (48x10 9 /L; range 130-400), increased d-dimer (27,546 ng/ml; normal value <500), and normal partial thromboplastin time (PTT; 24.9; range 24-38). Brain computed tomography (CT) and magnetic resonance imaging (MRI) identified an extended thrombosis involving left sigmoidal and transversal sinuses, rectus and inferior longitudinal sinuses without parenchymal damages. Serum anti-platelet factor 4 (PF4) IgG antibodies tested strongly positive (2.59 optical density; normal <0.4) confirming the hypothesis of a mechanisms mimicking heparin-induced thrombocytopenia. Enoxaparin 8,000 units were administered twice in 24 hours, then changed with fondaparinux. Four days later the clinical picture worsened with drowsiness, aphasia and right-side hemiparesis. Brain CT and MRI disclosed left-side temporal-occipital hypodensity with haemorrhagic infarctions. Platelet count remained low (range 37 to 45x10 9 /L) while PTT decreased below the lower normal value. Intravenous immunoglobulin (2 g/kg) was started. Over the following 5 days, the platelet count rapidly increased from 27x10 9 /L to 318x10 9 /L, while PTT normalized. The clinical picture significantly improved.Anti-PF4 antibody assay and high-dose IVIG therapy should be immediately considered in patients with vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) and thrombosis to avoid life-threatening complications.

Syncope at SARS-CoV-2 onset due to impaired baroreflex response (preprint)

We describe clinical and laboratory findings in 35 consecutive patients tested positive for SARS-CoV-2 by reverse transcriptase-polymerase chain reaction on nasopharyngeal swab that presented one or multiple syncopal events at disease onset. Neurological examination and electrocardiographic findings were normal. Chest computed tomography showed findings consistent with interstitial pneumonia. Arterial blood gas analysis showed low pO2, pCO2, and P/F ratio indicating hypocapnic hypoxemia, while patients did not show the expected compensatory heart rate increase. Such mechanism could have led to syncope. We speculate that SARS-CoV-2 could have caused angiotensin-converting enzyme-2 (ACE2) receptor internalization in the nucleus of the solitary tract (NTS), thus altering the baroreflex response and inhibiting the compensatory tachycardia during acute hypocapnic hypoxemia.

Gastrointestinal symptoms as Covid-19 onset in hospitalized Italian patients (preprint)

Objective To assess the prevalence of gastrointestinal symptoms and their correlation with need of non-invasive ventilatory support, intensive care unit admission and death in hospitalized SARS-CoV-2 patients. Design Since February 21th 2020, all individuals referred to our emergency department for suspected SARS-CoV-2 underwent a standardized assessment of body temperature and pulse oximetry, hematological screening, chest X-ray and/or computed tomography (CT), and SARS-CoV-2 assay on nasopharyngeal swab. Medical history and GI symptoms including nausea, vomit, diarrhea, and abdominal pain were recorded. Results GI symptoms were the main presentation in 42 (10.2%) of 411 patients, with a mean onset 4.9 +/-... days before admission. In 5 (1.2%) patients GI symptoms have not been associated with respiratory symptoms or fever. We found an inverse trend for ICU admission and death as compared with patients without GI symptoms. Conclusions GI symptoms can be an early and not negligible feature of Covid-19, and might be correlated with a more benign disease course.

SARS-COV-2 comorbidity network and outcome in hospitalized patients in Crema, Italy (preprint)

No systematic data on hospitalized SARS-COV-2 patients from Western countries are available. We report onset, course, correlations with comorbidities, and diagnostic accuracy of nasopharyngeal swab in 539 individuals suspected to carry SARS-COV-2 admitted to the hospital of Crema, Italy. All individuals underwent clinical and laboratory exams, SARS-COV-2 reverse transcriptase-polymerase chain reaction on nasopharyngeal swab, and chest X-ray and/or computed tomography (CT). Data on onset, course, comorbidities, number of drugs including angiotensin converting enzyme (ACE) inhibitors and angiotensin-II-receptor antagonists (sartans), follow-up swab, pharmacological treatments, non-invasive respiratory support, ICU admission, and deaths were recorded. Among 411 SARS-COV-2 patients (66.6% males) median age was 70.5 years (range 1-99). Chest CT was performed in 317 (77.2%) and showed interstitial pneumonia in 304 (96%). Fatality rate was 17.5% (74% males), with 6.6% in 60-69 years old, 21.1% in 70-79 years old, 38.8% in 80-89 years old, and 83.3% above 90 years. No death occurred below 60 years. Non-invasive respiratory support rate was 27.2% and ICU admission 6.8%. Older age, cough and dyspnea at onset, hypertension, cardiovascular diseases, diabetes, renal insufficiency, >7 drugs intake and positive X-ray, low lymphocyte count, high C-reactive protein, aspartate aminotransferase and lactate dehydrogenase values, and low PO2 partial pressure with high lactate at arterial blood gas analysis at admission were significantly associated with death. Use of ACE inhibitors or sartans was not associated with outcomes. Comorbidity network analysis revealed homogenous distribution of deceased and 60-80 aged SARS-COV-2 patients across diseases. Among 128 swab negative patients at admission (63.3% males) median age was 67.7 years (range 1-98). Chest CT was performed in 87 (68%) and showed interstitial pneumonia in 76 (87.3%). Follow-up swab turned positive in 13 of 32 patients. Using chest CT at admission as gold standard on the entire study population of 539 patients, nasopharyngeal swab had 80% sensitivity. SARS-CoV-2 caused high mortality among patients older than 60 years and correlated with pre-existing multiorgan impairment. ACE inhibitors and sartans did not influence patients' outcome.